Primary biliary cirrhosis (PBC) is an autoimmune disease3 of the liver characterized by inflammation of the bile ducts (here is the American Liver Foundation’s PBC information page). The immunity seems to be mainly targeted at mitochondrial antigens, which raises the question of why the liver is specifically involved — mitochondria are found in just about every cell type.

NKT cells recognize CD1, which binds to lipid-type antigens typical of bacterial cell walls. Bendalac’s group found that they could cause a PBC-like disease in mice by infecting them with a particular bacterium4 that is normally considered to be a fairly innocuous commensal. They tested this bacterium because it was previously shown to trigger antibodies that cross-react with the mitochondrial antigens that are targets in PBC. (Remember that mitochondria are historically extremely symbiotic bacteria, so the cross-reactivity doesn’t come completely out of the blue.)

Antibodies are produced by B cells. However, the disease could be blocked by preventing NKT cells from getting activated (by infecting mice lacking the NKT target, CD1). The rationale for doing this experiment was that innate immune responses to this particular bacterium are, a little unusually, normally driven by NKT cells.

The autoimmune-type disease lasted in these mice long after they had eliminated the bacteria — months, compared to a week or two to eliminate the actual infection. What’s more, even though NKT cells were essential to get the disease going, once it had started up, the disease could be transferred to new mice by swapping across classical T cells only (i.e. T cells but no NKT cells) — even into mice that had never seen the bacteria and didn’t even have CD1, which were doubly protected against having the disease start on its own. In other words, NKT cells start the disease, but don’t keep it going.

So what seems to be happening is that the NKT cells recognize the bacteria and produce massive inflammation. Because NKT cells tend to home to the liver5, they are able to overcome tolerance of cross-reactive cells in the liver, making liver antigens more at risk. The cross-reactive T and B cells, enraged by the constant roar of inflammation the NKT cells produce, attack the cross-reactive self antigens, damaging the cells and causing a constant inflammatory trigger. At this point the disease has become self-perpetuating, and you don’t need the NKT cells any more (and indeed, they quiet down about this time, as the bacteria are eliminated).

These findings establish the missing connection between the microbial innate immune trigger and chronic effector T and B lymphocyte attack of small bile ducts observed in PBC. 6

This is probably not a universal effect in detail — NKT cells are likely not important in the majority of autoimmune diseases — but it does give support to the general concepts that have been floating around for a while now.

Something I never quite understood about autoimmunity is why we need microbial antigens that mimic a host antigen, in addition to a danger signal. Shouldn’t any necrotic cell death, together with an inflammation, suffice? During necrosis, a lot of cellular components leak out, which are normally hidden from B-cells and could elicit an immune response. Apparently, this is not the case. Is this because of a previous ‘physiological leakage’ in the absence of a danger signal, making the immune system get used to intracellular antigens?

Kay, I don’t know either, and I think that it’s an open problem. In fact the whole mechanism is mostly hypothetical; as I say this is one of the few cases where even this many steps have been tracked through.

My own guess, belief, understanding, whatever you want to call it, is that there are quantitative differences in the stimulation, and qualitative differences in the antigen, that account for the pathogen requirement.

On the one hand most tissue damage that doesn’t involve infectious agents is transient; even if there is large-scale tissue damage it’s over in a short period (crush injuries, toxins) and then the inflammation starts to get cleared up. Pathogens are around longer, amplify their signal instead of attenuating it, and probably have a wider variety of signals. (I can think of exceptions to all of these, though.)

I would also suspect that pure self antigen is at least partially tolerized, whereas a microbial antigen that’s only partially similar might have only partial tolerance. For example, a single CTL epitope that partially cross-reacts, but that isn’t linked to CD4 epitopes for TRegs to see, might be more dangerous than a full-length self protein with suppressive epitopes linked to the activating ones. (In fact, thinking about it more, that seems to be a likely method of breaking tolerance.)

But at the end of the day (as always) “more research is needed” … which is one reason I’m submitting my autoimmunity grant application tomorrow.

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